'Bad' Osteoclasts Identified in Arthritis P at Hogenicity of Neutrophils Linked

RESEARCH HIGHLIGHTS BONE In mice with collagen antibody- induced arthritis, tamoxifen-mediated Precursors of ‘bad’ osteoclasts the cells deletion of Foxm1 alleviated bone expressed erosion and partially reduced the arthritis scores of the mice. Adoptive identified in arthritis FOXM1 and transfer of Foxm1-expressing Osteoclasts are important for both distinct from osteoclast precursors had a high monocytes partially reversed these homeostatic bone remodelling in involved in homeostatic bone osteoclasto- effects. health and pathological bone erosion remodelling in the bone marrow. genic potential Notably, the researchers identified in rheumatoid arthritis (RA), but Transcriptional profiling a population of macrophages in the whether different types of osteoclasts implicated the transcription factor synovium of patients with RA that mediate these two processes is FOXM1 as an important regulator corresponded to mouse AToMs. unclear. New findings suggest that of AtoMs. Indeed, treatment with The cells expressed FOXM1 and had osteoclasts in these different tissue thiostrepton (an inhibitor of FOXM1 a high osteoclastogenic potential settings arise from different precursor activity) inhibited osteoclastogenesis that was inhibited with thiostrepton cells and hence follow distinct of AtoMs in vitro. In mice with in vitro. developmental trajectories. CIA, thiostrepton treatment reduced The researchers plan to develop a To identify osteoclast precursor the arthritis scores of the mice novel therapy that specifically targets cells in the synovium, researchers in a and inhibited the expression of these ‘bad’ osteoclast precursors. new study developed a protocol that pro-inflammatory cytokines in the “Because current regimens for enabled them to isolate synovium synovium. However, in healthy treating bone diseases block both from ‘bare areas’ of the joint (areas mice, thiostrepton had no effect on ‘good’ and ‘bad’ osteoclasts, a new where the synovium comes into homeostatic bone remodelling. line of therapy targeting only ‘bad’ contact with bone). They detected ones would be meritorious for future a subpopulation of macrophages patient care,” explains corresponding (termed arthritis- associated osteo- author Masaru Ishii. clastogenic macrophages (AtoMs)) in Jessica McHugh the inflamed synovium of mice with ORIGINAL artiCLE Hasegawa, T. et al. collagen- induced arthritis (CIA). Identification of a novel arthritis-associated This population contained osteoclast osteoclast precursor macrophage regulated by FoxM1. Nat. Immunol. 20, 1631–1643 (2019) precursors that were phenotypically Credit: N. Smith/Springer Nature Limited SYSTEMIC LUPUS ERYTHEMATOSUS P at hogenicity of neutrophils linked to maturation stage in SLE Dysregulated neutrophils have a immune dysregulation in SLE,” explains pathogenic features of LDGs and was pathogenic role in systemic lupus Mariana Kaplan, corresponding responsible for the type I interferon erythematosus (SLE), in particular intermediate- author of a new study on LDGs. gene signature in SLE,” says Kaplan. through the release of neutrophil Little was previously known about Interestingly, high numbers of extracellular traps (NETs) and the mature LDGs the heterogeneity of LDGs and intermediate-mature LDGs in the blood subsequent production of type I in the blood of whether subsets existed with distinct of patients with SLE correlated with interferon. However, exactly how patients with pathogenic functions. To address these more severe organ damage, reduced neutrophils become dysregulated uncertainties, Kaplan and colleagues kidney function and an increased in SLE is an active area of research. SLE correlated used a range of transcriptomic coronary plaque burden. The results “Our group had previously identified with more and epigenomic approaches to of further in vivo and in vitro studies a pro-inflammatory neutrophil subset severe organ characterize LDGs from patients also suggested a role for these cells known as low-density granulocytes with SLE. Notably, they identified in vascular damage. (LDGs). We found that these cells could damage two subsets that seemed to represent “Future studies will focus on damage blood vessels and promote different stages of LDG maturation identifying potential therapies and that could be distinguished that can specifically target the by their expression of CD10 — intermediate-mature LDG subset CD10− immature LDGs and CD10+ in the treatment and/or prevention intermediate-mature LDGs. of lupus vasculopathy and premature The researchers went on to cardiovascular disease in SLE,” functionally characterize these states Kaplan. subsets by examining their ability to Joanna Clarke perform typical neutrophil tasks such ORIGINAL artiCLE Mistry, P. et al. Transcriptomic, as degranulation, NET production and epigenetic, and functional analyses implicate phagocytosis. “Overall, we found that neutrophil diversity in the pathogenesis of systemic the intermediate-mature subpopulation lupus erythematosus. Proc. Natl Acad. Sci. USA 116, 25222–25228 (2019) Credit: Nicholas Mayeux/Stocktrek Images of LDGs displayed the bulk of the NATURE REVIEWS | RHEUMATOLOGY VOLUME 16 | FEBRUARY 2020 | 63.

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